Belén Valenzuela1, Juan-José Pérez-Ruixo2, Quentin Leirens3,4, Sivi Ouwerkerk-Mahadevan5, Italo Poggesi6. 1. Janssen-Cilag Spain, Part of Janssen Pharmaceutical Companies of Johnson and Johnson, Madrid, Spain. BValenz2@ITS.JNJ.com. 2. Janssen-Cilag Spain, Part of Janssen Pharmaceutical Companies of Johnson and Johnson, Madrid, Spain. 3. SGS Exprimo, part of SGS Belgium NV, Mechelen, Belgium. 4. Pharmetheus AB, Uppsala, Sweden. 5. Janssen Research and Development, Beerse, Belgium. 6. Janssen-Cilag Italy, part of the Janssen Pharmaceutical Companies of Johnson and Johnson, Cologno Monzese, Italy.
Abstract
OBJECTIVE: The aim of this study was to characterize the relationship between ponesimod plasma concentrations and the temporal evolution of lymphocyte counts in multiple sclerosis (MS) patients. METHODS: Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models were developed using data from phase I, II, and III trials, and the impact of clinically relevant covariates on PK and PD parameters was assessed. Simulations were conducted to evaluate the maximal lymphocyte count reduction after ponesimod treatment, and the time required for total lymphocyte counts to return to normal values after treatment interruption. RESULTS: In MS patients, ponesimod PK were characterized by a low mean apparent plasma clearance (5.52 L/h) and a moderate mean apparent volume of distribution at steady state (239 L). The model developed indicated that none of the evaluated covariates (age, sex, formulation, food, body weight, clinical condition, and renal impairment) had a clinically relevant impact on the PK/PD parameters. In MS patients, total lymphocyte counts were characterized by a maximum reduction of 88.0% and a half maximal inhibitory concentration (IC50) of 54.9 ng/mL. Simulations indicated that in patients with normal hepatic function treated with ponesimod 20 mg daily, total lymphocyte counts were reduced to 41% of baseline at trough. After stopping treatment, lymphocyte counts were restored to normal levels within one week. CONCLUSIONS: The population PK/PD model well-characterized the PK of ponesimod and the time course of total lymphocyte counts in MS patients. Additionally, none of the evaluated covariates had a clinically relevant impact. This should be taken into consideration when assessing the risk of infection, administration of live-attenuated vaccines, and concomitant use of immunosuppressants.
OBJECTIVE: The aim of this study was to characterize the relationship between ponesimod plasma concentrations and the temporal evolution of lymphocyte counts in multiple sclerosis (MS) patients. METHODS: Population pharmacokinetic (PK) and PK/pharmacodynamic (PD) models were developed using data from phase I, II, and III trials, and the impact of clinically relevant covariates on PK and PD parameters was assessed. Simulations were conducted to evaluate the maximal lymphocyte count reduction after ponesimod treatment, and the time required for total lymphocyte counts to return to normal values after treatment interruption. RESULTS: In MS patients, ponesimod PK were characterized by a low mean apparent plasma clearance (5.52 L/h) and a moderate mean apparent volume of distribution at steady state (239 L). The model developed indicated that none of the evaluated covariates (age, sex, formulation, food, body weight, clinical condition, and renal impairment) had a clinically relevant impact on the PK/PD parameters. In MS patients, total lymphocyte counts were characterized by a maximum reduction of 88.0% and a half maximal inhibitory concentration (IC50) of 54.9 ng/mL. Simulations indicated that in patients with normal hepatic function treated with ponesimod 20 mg daily, total lymphocyte counts were reduced to 41% of baseline at trough. After stopping treatment, lymphocyte counts were restored to normal levels within one week. CONCLUSIONS: The population PK/PD model well-characterized the PK of ponesimod and the time course of total lymphocyte counts in MS patients. Additionally, none of the evaluated covariates had a clinically relevant impact. This should be taken into consideration when assessing the risk of infection, administration of live-attenuated vaccines, and concomitant use of immunosuppressants.
Authors: Ludwig Kappos; Robert J Fox; Michel Burcklen; Mark S Freedman; Eva K Havrdová; Brian Hennessy; Reinhard Hohlfeld; Fred Lublin; Xavier Montalban; Carlo Pozzilli; Tatiana Scherz; Daniele D'Ambrosio; Philippe Linscheid; Andrea Vaclavkova; Magdalena Pirozek-Lawniczek; Hilke Kracker; Till Sprenger Journal: JAMA Neurol Date: 2021-05-01 Impact factor: 18.302